Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA.
Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA.
Am J Ophthalmol. 2021 Jan;221:246-259. doi: 10.1016/j.ajo.2020.07.021. Epub 2020 Jul 21.
To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach.
Genetic association cohort study.
Setting: Single-center study at an academic referral center.
164 patients with clinically diagnosed uveitis of the posterior segment.
Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling, and in silico calculations were then used to rank and predict the functional consequences of key variants.
A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis-such as NOD2 (Blau syndrome) and CAPN5 NIV (neovascular inflammatory vitreoretinopathy)-as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type.
This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole-exome sequencing can help diagnose nonsyndromic uveitis in patients harboring known variants for syndromic inflammatory diseases.
采用功能基因组学方法阐明后节葡萄膜炎的分子危险因素。
遗传关联队列研究。
地点：学术转诊中心的单中心研究。
164 例临床诊断为后节葡萄膜炎的患者。
外显子组测序用于检测 164 例后节葡萄膜炎患者中发现的变异。然后，采用表型驱动分析、蛋白质结构建模和计算机模拟计算对关键变异进行排序和预测其功能后果。
本研究共纳入 164 例患者的 23 个基因中的 203 个单核苷酸变异。在所研究的基因中，既发现了已知的变异，也发现了以前与特定类型综合征性葡萄膜炎（如 NOD2[Blau 综合征]和 CAPN5 NIV[新生血管性炎症性玻璃体视网膜病变]）相关的基因中的新型变异，以及以前与后节葡萄膜炎无关的基因中的变异。基于排序列表和蛋白质-蛋白质相互作用网络，通过结构建模和计算机模拟计算对 NOD 样受体家族基因（NOD2、NLRC4、NLRP3 和 NLRP1）、CAPN5 和 TYK2 中的错义变异进行了特征描述，以预测特定变异如何改变蛋白质结构和功能。分析的大多数变异与野生型明显不同。
本研究提示了可能与后节葡萄膜炎易感性相关的新途径和免疫信号蛋白。更大的队列和功能研究将有助于验证所鉴定突变的致病性。在特定情况下，全外显子组测序有助于诊断携带综合征性炎症性疾病已知变异的患者的非综合征性葡萄膜炎。
